Cachexia: Common, Deadly, With an Urgent Need for Precise Definition and New Therapies

doi:10.1016/j.amjcard.2008.02.065

The American Journal of Cardiology

Volume 101, Issue 11, Supplement, 2 June 2008, Pages S8-S10

https://doi.org/10.1016/j.amjcard.2008.02.065 Get rights and content

Cachexia—sometimes also referred to as wasting disease, malnutrition, or hypercatabolism—has been described for centuries and has always raised ominous thoughts that “the end is near.” The disease is encountered in many malignant and nonmalignant chronic, ultimately fatal, illnesses. Yet, although cachexia is a deadly syndrome, little is known about its pathophysiology, and the debate regarding its definition is ongoing. Thus, the data on epidemiology can be contested, but a few things are certain: Cachexia is associated with exceedingly high mortality once the syndrome has fully developed, irrespective of the definition we apply, and it is associated with weakness, weight loss, muscle wasting, and inflammation. It is not simply an ancillary event, and it may contribute to the death of the patient either through effects on neuroendocrine and immune defense mechanisms or through protein calorie malnutrition. The therapeutic standard of care for cachexia remains undefined to date, with a few exceptions. Among the recognized approaches, exogenous oral amino acid supplementation appears very promising. Further research efforts are needed and they are ongoing.

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Author Disclosures

The authors who contributed to this article have disclosed the following industry relationships:

Mitja Lainscak, MD, PhD, has no financial arrangement or affiliation with a corporate organization or a manufacturer of a product discussed in this supplement.

Gerasimos S. Filippatos, MD, has received research/grant support from GlaxoSmithKline, Medtronic, Inc., Otsuka Pharmaceutical Co., and Vifor International Inc.

Mihai Gheorghiade, MD, serves as a consultant to Debbio Pharm, ErreKappa

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Loss of fat tissue is also thought to be a key-factor in the pathophysiology of cachexia even though fat, unlike muscle, cannot generate its own thermic energy. In industrialized countries where the overall prevalence is growing approximately up to 1% (i.e., about nine million patients), cachexia develops in many chronic conditions including cancer, chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), chronic kidney disease, rheumatoid arthritis, stroke and infectious diseases such as HIV/AIDS, malaria, and tuberculosis [4,5] (Table 2). Based on population prevalence, cachexia ranges from 5% to 15% in CHF or COPD to 60–80% in advanced cancer [4].
Cachexia is a public health challenge around the Globe but data on prevalence rates in developing countries are very scarce. In sub-Saharan Africa wasting syndrome is mainly related to malaria, HIV infections, tuberculosis and end-stage heart disease and always associated with high-mortality and dismal quality of life regardless of age, urban or rural setting. We report two different cases affected by cardiac cachexia related to end-stage heart disease. The large age gap between patients highlights the current impact of medical services in Uganda ranging from low-resource rural settings to urban areas of the capital city under epidemiologic transition. The wasting syndrome occurring in both patients emphasizes as cachexia remains largely neglected and underestimated in most sub-Saharan African countries.
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Prealbumin is a maker of nutritional status and inflammation of potential prognostic value in acute heart failure (HF). The aim of this study is to evaluate if low prealbumin levels on admission predict mortality and readmissions in patients with acute HF.
We conducted a prospective observational cohort study including 442 patients hospitalized for acute HF. Patients were classified in two groups according to prealbumin levels: “normal” prealbumin (> 15 mg) and “low” prealbumin (≤ 15 mg/dL). End-points were mortality and readmissions (all-cause and HF-related) and the combined end-point of mortality/readmission at 180 days.
Out of 442 patients, 159 (36%) had low and 283 (64%) had normal prealbumin levels Mean age was 79.6 (73.9–84.2, p = 0,405) years and 183 (41%, p = 0,482) were males. After a median 180 days of follow-up, 108 (24%, p = 0,021) patients died and 170 (38%, p = 0,067) were readmitted. Mortality was higher in the low prealbumin group. The combined end-point was more frequent in the low prealbumin group (57% vs. 50%, p = 0.199). In the multivariate analysis the following variables were associated with mortality or readmission: older age, exacerbated chronic HF, higher comorbidity, low systolic blood pressure and hemoglobin values and higher pro brain natriuretic peptide levels.
Low prealbumin is common (36%) in patients with acute heart failure and it is associated with a higher short-term mortality.
Cerebrosides from sea cucumber ameliorates cancer-associated cachexia in mice by attenuating adipose atrophy
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Cancer-associated cachexia (CAC) is a multifactorial wasting syndrome which impairs quality of cancer patients' life. Cerebrosides, a principal class of sphingolipids, have various biological actions such as anti-tumour effects. In this study, we found that a continuous oral administration of cerebrosides obtained from sea cucumber Acaudina molpadioides (AMC) at 50 mg/kg body mass per day suppressed body weight loss through alleviating adipose atrophy in CAC mice. The possible mechanism by which dietary AMC prevents adipose atrophy in CAC mice was related to reducing serum inflammatory cytokine levels, regulating over-lipolysis, enhancing the function of lipogenesis and decreasing the lipid over-utilization. To elucidate the structure–activity relationships of AMC and its long-chain base (LCB), we also compared the anti-tumour activities between them. The results indicated that LCB exhibited more prominent anti-tumour effect both in vivo and in vitro. Therefore, AMC and its LCB are highly worth developing as novel agents for cancer therapy.
Prealbumin improves death risk prediction of BNP-added Seattle Heart Failure Model: Results from a pilot study in elderly chronic heart failure patients
2013, International Journal of Cardiology
Citation Excerpt :
Prealbumin, also known as transthyretin, is a globular, non-glycosilated protein, synthesized by the liver, and complexed with a retinol-binding protein, which acts as a transporter of retinol/vitamin A (90–95%) and thyroid hormones (20%), and its levels may be lowered not only by undernutrition, but also by inflammation and aging [24,25]. Low plasma prealbumin level has far-back emerged as an earliest laboratory indicator of poor nutritional status [24] but its additive prognostic power to SHFM and BNP combined in CHF patients has never been reported until now and it strongly supports the known prognostic relevance of malnutrition and cachexia development in this patient population [11,26,27]. In our study a positive linear relationship was observed between prealbumin levels and BMI (r = 0.38, P < 0.01), thus emphasizing the importance of the reverse epidemiology phenomenon in heart failure.
An accurate prognosis prediction represents a key element in chronic heart failure (CHF) management. Seattle Heart Failure Model (SHFM) prognostic power, a validated risk score for predicting mortality in CHF, is improved by adding B-type natriuretic peptide (BNP). We evaluated in a prospective study the incremental value of several biomarkers, linked to different biological domains, on death risk prediction of BNP-added SHFM.
Troponin I (cTnI), norepinephrine, plasma renin activity, aldosterone, high sensitivity-C reactive protein (hs-CRP), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), interleukin 2 soluble receptor, leptin, prealbumin, free malondialdehyde, and 15-F_2t-isoprostane were measured in plasma from 142 consecutive ambulatory, non-diabetic stable CHF (mean NYHA-class 2.6) patients (mean age 75 ± 8 years). Calibration, discrimination, and risk reclassification of BNP-added SHFM were evaluated after individual biomarker addition.
Individual addition of biomarkers to BNP-added SHFM did not improve death prediction, except for prealbumin (HR 0.49 CI: (0.31–0.76) p = 0.002) and cTnI (HR 2.03 CI: (1.20–3.45) p = 0.009). In fact, with respect to BNP-added SHFM (Harrell's C-statistic 0.702), prealbumin emerged as a stronger predictor of death showing the highest improvement in model discrimination (+ 0.021, p = 0.033) and only a trend was observed for cTn I (+ 0.023, p = 0.063). These biomarkers showed also the best reclassification statistic (Integrated Discrimination Improvement—IDI) at 1-year (IDI: cTnI, p = 0.002; prealbumin, p = 0.020), 2-years (IDI: cTnI, p = 0.018; prealbumin: p = 0.006) and 3-years of follow-up (IDI: cTnI p = 0.024; prealbumin: p = 0.012).
Individual addition of prealbumin allows a more accurate prediction of mortality of BNP enriched SHFM in ambulatory elderly CHF suggesting its potential use in identifying those at high-risk that need nutritional surveillance.
Mechanism and novel therapeutic approaches to wasting in chronic disease
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Citation Excerpt :
Other candidate targets for therapeutic interventions include transcription factors and their stimulators, neurohormonal antagonists, and anti-inflammatory drugs. To date, we are left with little guidance how to treat our cachexia patients, until results of ongoing studies are available, aggressive therapy of cachexia inducing illness and comorbid conditions appears as best possible practice [82]. Nicole Ebner wrote the first draft of the manuscript and all authors provided guidance and assistance in the writing and editing of the manuscript; and gave sagely advice.
Cachexia is a multifactorial syndrome defined by continuous loss of skeletal muscle mass – with or without loss of fat mass – which cannot be fully reversed by conventional nutritional support and which may lead to progressive functional impairment and increased death risk. Its pathophysiology is characterized by negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. Muscle wasting is encountered in virtually all chronic disease states in particular during advanced stages of the respective illness. Several pre-clinical and clinical studies are ongoing to ameliorate this clinical problem. The mechanisms of muscle wasting and cachexia in chronic diseases such as cancer, chronic heart failure, chronic obstructive pulmonary disease and chronic kidney disease are described. We discuss therapeutic targets and such potential modulators as appetite stimulants, selective androgen receptor modulators, amino acids and naturally occurring peptide hormones.

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: Statement of author disclosure: Please see the Author Disclosures section at the end of this article.

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Cachexia: Common, Deadly, With an Urgent Need for Precise Definition and New Therapies

Section snippets

Author Disclosures

Int J Cardiol

Int J Cardiol

Am J Clin Nutr

Clin Nutr

Int J Cardiol

Semin Nephrol

Am J Clin Nutr

Int J Biochem Cell Biol

Lancet

Lancet

Int J Cardiol

J Am Coll Cardiol

Am Heart J